Description: Osteoarthritis (OA) is a debilitating condition of articular joints. Arthritis is the 3rd most prevalent health problem in the Veterans population affecting 43% of VA system users and veterans are ~36% more likely to be affected by OA as compared to the general population. This proposal will utilize preclinical models of osteoarthritis and test the efficacy of regenerative stem cell therapies in combination with rehabilitation regimens. The overall objective of the proposed study is to examine the progression of cartilage degeneration and changes in functional capacities under contrasting loading conditions with and without the therapeutic benefits of MSCs using a well-established injury/surgery induced knee OA model in rats. Our overall hypothesis is that while reduced joint loading will remain detrimental to cartilage health, an elevated joint load will instead enhance the therapeutic effects of MSCs on attenuating PTOA following traumatic knee injuries. Research Plan: To address the above objective we have developed two aims: Aim 1: {To establish the effects of altered knee loading via non-weight bearing or running on cartilage degeneration, joint kinematics during locomotion, and degree of voluntary activity in rats following a medial meniscal transection (MMT) surgery. Aim 2: To examine how altered knee loading (via non-weight bearing or running) influences the efficacy of MSC treatment on cartilage degeneration, joint kinematics during locomotion, and degree of voluntary activity in rats following MMT.} Methods: The rat MMT-induced OA model will be used for this study. Allogeneic MSCs or saline (control) will be administered via intra-articular injection one day post-surgery to assess the effects on the onset of OA (Aim 1). Rats in both injection groups will then be randomly assigned to the following 3 loading conditions: 1) regular loading, 2) non-weight bearing via hind limb suspension, and 3) daily treadmill running. Rats will be tested and sacrificed at the end of the 8th week post-injury to assess the changes in 3D microstructure and composition in the knee articular cartilage using our previously developed EPIC-CT and validated with histology. To assess functional capacities rats will be evaluated at pre-surgery and 2, 4, 6, and 8 weeks post-surgery. At each time point, we will assess the level of voluntary activity by quantifying the amount (time and distance) of running on a wheel mounted inside the cage. We will quantify 3D lower limb kinematics (i.e., hip, knee, and ankle angles) during treadmill locomotion using a high-speed X-ray motion analysis system. We anticipate the proposed research will result in new insights on regenerative rehabilitation protocols for veterans with OA and will be communicated through publications and our clinical consultants in order to impact military and Veterans care.